Method and apparatus for delivery of therapeutic agents

ABSTRACT

Methods and apparatus for the reproducible, consistent and efficacious delivery of a therapeutic agent to a patient. The invention comprises means for the controlled administration of the therapeutic agent through an orifice to the patient, a plurality of penetrating electrodes arranged with a predetermined spatial relationship relative to the orifice, and means for generating an electrical signal operatively connected to the electrodes.

TECHNICAL FIELD

The present invention is directed to the delivery of prophylactic andtherapeutic agents to patients and, more particularly, to thereproducible, consistent, and efficacious delivery of prophylactic andtherapeutic agents, such as nucleic acids, drugs, and proteins, todefined regions in selected tissues of interest.

BACKGROUND OF THE INVENTION

Prophylactic and therapeutic agents have long been delivered to patientsusing various conventional routes of administration, such as topical,oral, intravenous, parenteral, and the like. Once administered to thepatient by the selected route, the delivery of the agent to the tissueof interest and its beneficial interaction with the tissue is largelydependent on its inherent physicochemical factors, but may have beenfacilitated by, for example, selected components of the deliverycomposition such as carriers, adjuvants, buffers and excipients, and thelike.

More recently, the application of electrical signals has been shown toenhance the movement and uptake of macromolecules in living tissue.Application of such electrical signals in tissue relative to theadministration of a prophylactic or therapeutic agent can have desirableeffects on the tissue and/or the agent to be delivered. Specifically,techniques such as electroporation and iontophoresis have been utilizedto significantly improve the delivery and/or uptake of a variety ofagents in tissue. Such agents include pharmaceuticals, proteins, andnucleic acids. Potential clinical applications of such techniquesinclude the delivery of chemotherapeutic drugs and/or therapeutic genesin tumors, the delivery of DNA vaccines for prophylactic and therapeuticimmunization, and the delivery of nucleic acid sequences encodingtherapeutic proteins.

Many devices have been described for the application of electricalsignals in tissue for the purpose of enhancing agent delivery. The vastmajority of these have focused on a means for effective application ofthe electrical signals within a target region of tissue. A variety ofsurface and penetrating electrode systems have been developed forgenerating the desired electrophysiological effects.

In spite of the promise associated with electrically mediated agentdelivery and the potential clinical applications of these techniques,progress has been hampered by the lack of an effective means to achievethe overall objective of efficient and reliable agent delivery usingthese techniques. One of the most significant shortcomings of currentsystems is the inability to achieve reliable and consistent applicationfrom subject to subject. Significant sources of this variability are dueto differences in the technique and skill level of the operator. Othersources of variability that are not addressed by current systems includedifferences in the physiologic characteristics between patients that canaffect the application of the procedure.

Given that reliable and consistent application of clinical therapies ishighly desirable, the development of improved application systems iswell warranted. Such development should include a means for minimizingoperator-associated variability while providing a means to accommodatethe differences in patient characteristics likely to be encounteredduring widespread clinical application of electrically mediated agentdelivery.

DISCLOSURE OF THE INVENTION

The present invention provides improved methods and apparatus for thereproducible, consistent, and efficacious delivery of therapeuticagents, such as nucleic acids, drugs, and proteins, to patientsutilizing Electrically Mediated Therapeutic Agent Delivery.

In one aspect, the present invention provides an apparatus for thedelivery of a therapeutic agent to a predetermined site within a patientcomprising means for the controlled administration of the therapeuticagent to the patient comprising a reservoir for the therapeutic agent,at least one orifice through which the agent is administered, and acontrolled source of energy sufficient to transfer a predeterminedamount of the therapeutic agent at a predetermined rate from thereservoir through the orifice to the predetermined site within thepatient. In addition, the apparatus comprises a plurality of penetratingelectrodes arranged with a predetermined spatial relationship relativeto the orifice, and means for generating an electrical signaloperatively connected to the electrodes.

Other aspects of the invention include methods comprising TherapeuticAgent Administration in controlled spatial and temporal conjunction withElectric Signal Administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A–C are graphic depictions of potential sources of spatialvariability associated with conventional needle syringe injection;

FIG. 2 is a cross sectional depiction of an embodiment of an apparatusof the invention comprising an integrated means for therapeutic agentadministration and electrical signal application;

FIG. 3 is a cross sectional depiction of an alternative embodiment of anapparatus of the invention comprising an integrated means fortherapeutic agent administration and electrical signal application;

FIG. 4A is a cross sectional view of a portion of an embodiment of theinvention during therapeutic agent administration;

FIG. 4B is a bottom view of the embodiment of FIG. 4A, depicting theportion of the device which interfaces with the tissue of a patient;

FIGS. 5A–D illustrate several embodiments of embodiments of theinvention depicting the portion of the apparatus that interfaces withthe tissue of a patient;

FIG. 6A is a partial cross sectional view of a further alternativeembodiment of an apparatus of the invention comprising an integratedmeans for therapeutic agent administration and electrical signalapplication;

FIG. 6B is a bottom plan view of the embodiment of FIG. 6A, depictingthe portion of the device which interfaces with the tissue of a patient;and

FIG. 7 is a block diagram of a treatment system in accordance with theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides improved methods and apparatus for thereproducible, consistent, and efficacious delivery of therapeuticagents, such as nucleic acids, drugs, and proteins, with ElectricallyMediated Therapeutic Agent Delivery (EMTAD).

In one aspect, the present invention provides an apparatus for thedelivery of a therapeutic agent to a predetermined site within a patientcomprising means for the controlled administration of the therapeuticagent to the patient comprising a reservoir for the therapeutic agent,at least one orifice through which the agent is administered, and acontrolled source of energy sufficient to transfer a predeterminedamount of the therapeutic agent at a predetermined rate from thereservoir through the orifice to the predetermined site within thepatient. In addition, the apparatus comprises a plurality of penetratingelectrodes arranged with a predetermined spatial relationship relativeto the orifice, and means for generating an electrical signaloperatively connected to the electrodes.

In the present invention, EMTAD is defined as the application ofelectrical signals to biological tissue for the purpose of enhancingmovement and/or uptake of a therapeutic agent in tissue. The process ofEMTAD is comprised of two elements: 1) Therapeutic Agent Administration(TAA), and 2) an Electrical Signal Application (ESA) sufficient toinduce the desired EMTAD effect. In the present invention, therapeuticagent administration is accomplished in a controllable fashion, termedControlled Therapeutic Agent Administration (CTAA). The term CTAA usedherein refers to methods and apparatus capable of providing spatial andtemporal control over administration of a therapeutic agent relative tothe induction of an EMTAD effect. Controllable administration techniquesmay utilize variations on the conventional needle-syringe (e.g.automatic injection device) and/or various needleless methodologies(e.g. jet injector, transdermal/transcutaneous patch, oral, gel, cream,or inhaled administration). The term ESA used herein refers to theapplication of electrical signals to facilitate or enhance the deliveryof therapeutic agents by improving movement and/or uptake of said agentswithin tissue, thus inducing an EMTAD effect. When used to facilitate orenhance delivery of a therapeutic agent, ESA processes such aselectroporation, iontophoresis, electroosmosis, electropermeabilization,electrostimulation, electromigration, and electroconvection allrepresent various modes of EMTAD.

Specific applications for EMTAD include, but are not limited to, thedelivery of vaccines, therapeutic proteins, and chemotherapeutic drugs.Traditionally with such applications, EMTAD is initiated by therapeuticagent injection using a conventional needle-syringe. After the agent hasbeen administered, a device suitable for ESA is applied to the patientat a designated location. Finally, an appropriate ESA protocol isutilized to provide the desired facilitation or enhancement totherapeutic agent delivery. With traditional EMTAD, however, the desiredspatial and temporal relationship between agent administration and ESAmay not be realized.

Spatial Parameters

For agents in which the use of EMTAD is not required or desirable,therapeutic agent administration is often performed using a conventionalneedle syringe. While the therapeutic objectives can usually beaccomplished using these means, the need to deliver certain agents withEMTAD brings an additional level of complexity to the issue of TAA. Asdepicted in FIG. 1, in any conventional needle-syringe injection, as theneedle 5 is inserted into the tissue, the depth 1 and the angle 2 ofinsertion relative to the surface of the tissue 3 can be difficult tocontrol. Additionally, the point of needle penetration 4 at the tissuesurface 3 may not be representative of the location of the orifice 6 andthe region of agent administration 7 within the target tissue. As anillustrative example a transcutaneous intramuscular injection may notcorrespond to the site of insertion on the skin since the two tissuescan often move in relation to one another.

While this conventional approach is generally adequate for the deliveryof many different therapeutics that do not require EMTAD, thesevariables lead to a distribution of the therapeutic agent followinginjection that is often inconsistent and/or indeterminate and can hampereffective EMTAD. Commonly, the most effective use of EMTAD utilizes apredefined relationship between the therapeutic agent and ESA within thepatient. As a result, the lack of spatial control over TAA in a targettissue using a conventional needle syringe can hamper the outcome of theEMTAD application. One illustrative example of this concept is the useof electroporation to facilitate the delivery of a therapeutic agent.Electroporation is typically most effective in enhancing therapeuticagent delivery when TAA and ESA are co-localized within the targetregion of tissue. In many cases, if the agent to be delivered and theinduced electroporation effect are not co-localized within the targetregion of tissue, the delivery of said agent is suboptimal.

Another example of the need for adequate spatial control of TAA in EMTADis iontophoresis. This mode of EMTAD uses electrical fields to causemovement of charged molecules. In order to achieve the desired movementof the agent, the proper spatial relationship between the electrodes andthe therapeutic agent must be realized. If a negatively charged agentwere placed in close proximity to the location of a positive electrode,little or no movement of the agent through the tissue would be observed.In contrast, localization of the said negatively charged agent near thenegative electrode would result in significant movement of the agentthrough the tissue in the direction of the positive electrode.

As illustrated by the preceding examples, care must be taken to controlthe precise location of TAA relative to the application of ESA toachieve the desired effect. As a result, methods for achievingreproducible, consistent, and well-characterized distribution of thetherapeutic agents are highly desirable.

Temporal Parameters

Another disadvantage with conventional needle-syringe injection TAA isthat the rate of injection may vary from one operator to another,thereby causing inconsistent agent distribution in the tissue.Additional temporal variability is introduced when multiple deviceplacements are required to complete the EMTAD process. For example, oneapplication of EMTAD calls for the administration of plasmid DNAencoding for a therapeutic protein, followed by generation of anelectroporation-inducing electrical field. Using the traditional methodof EMTAD, the plasmid is injected with a needle-syringe, followed byplacement and activation of the electroporation device. By requiring twoseparate device placements (the initial needle syringe followed by theESA device), this procedure is susceptible to inter-patient variabilityarising from inconsistent temporal application of each device by theoperator. Additionally, the use of two separate device placements leadsto an unavoidable time interval in between the clinician's placement andactivation of each device. This is compounded in the case where multipleapplication sites are necessary to achieve adequate delivery of theagent to a specifiable region within the target tissue.

These issues are especially critical for agents, such as nucleic acids,that can be degraded or inactivated in the extracellular environment.Therapeutic agent degradation can lead to a reduction in efficacy andconsistency in the application of the therapy. Also, the inter-patientrate of therapeutic agent degradation is not constant, thus contributingto the overall therapeutic inconsistency of conventional needle-syringeinjection combined with ESA, and more specifically with electroporationtherapy.

Due to the inherent difficulty of spatial and temporal variability withconventional needle-syringe injection used in conjunction with ESA, theprecise location and timing of TAA relative to ESA is often unknown. Asa result, the effective administration and dosing of therapeutic agentswith EMTAD may be inconsistent and irreproducible. Though conventionalneedle-syringe injection is sometimes adequate for therapeutic agentadministration, reproducible and consistent agent delivery issignificantly enhanced by controlling the spatial and temporalrelationship between administration of the therapeutic agent andinduction of the desired EMTAD effect.

Thus, while the traditional EMTAD procedure may be adequate for certainapplications, temporal and spatial control is highly desirable forclinical applications that typically require a high degree ofconsistency and reproducibility. In contrast to the conventional EMTADapproach previously described, several techniques for combined CTAA andESA are described herein to provide more advantageous methods andapparatus for the clinical application of EMTAD. The present inventionutilizes various aspects of CTAA in conjunction with ESA to providereproducible, consistent, and efficacious therapeutic agent delivery.More specifically, this invention describes methods and apparatus toprovide spatial and temporal control over administration of atherapeutic agent relative to the application of electrical signals,thereby improving the movement and/or uptake of said agent in the targettissue.

In the present invention, there exists a controllable spatialrelationship for the administration of the therapeutic agent relative tothe application of electrical signals. Prior to treatment, the optimallocation for TAA relative to ESA is determined. This spatialrelationship between TAA and ESA is dictated by treatment parameters,including the nature of the agent being administered and the propertiesof the target tissue to which the agent is administered. In certainapplications, electrical signals are preferentially applied distal tothe site of therapeutic agent administration. However, the typicalspatial relationship is to apply the EMTAD-inducing electrical signalsproximal to the site of agent administration. In the practice of suchapplications, co-localization between TAA and ESA may be preferential.This is often the case when electroporation and/or iontophoresis areutilized for induction of the desired EMTAD effect.

Another aspect of the invention provides a controllable temporalrelationship for the sequence and timing of TAA relative to ESA. Priorto treatment, the optimal sequence and timing for combination of TAA andESA is determined. As with the spatial relationship, the desiredtemporal relationship between TAA and ESA is dictated by parameters suchas the nature of the agent being administered and the properties of thetarget tissue to which the agent is administered. In certainapplications, exposure to the electrical fields associated with ESA mayadversely affect the therapeutic agent. In the practice of suchapplications, generation of such electrical fields is followed by CTAA.However, the typical temporal relationship is CTAA followed by ESA.

The present invention provides improved methods and apparatus for thereproducible, consistent, and efficacious delivery of therapeuticagents, such as nucleic acid based constructs, pharmaceutical compounds,drugs, and proteins, with EMTAD. This objective is accomplished bycontrolling the spatial and temporal administration of a therapeuticagent relative to application of electrical signals. Specificapplications for EMTAD include, but are not limited to, the delivery ofvaccines, therapeutic proteins, and chemotherapeutic drugs.Traditionally with such applications, EMTAD is initiated by therapeuticagent injection using a conventional needle-syringe. After the agent hasbeen administered, a device suitable for ESA is applied to the patientat a designated location. Finally, an appropriate ESA protocol isutilized to provide the desired facilitation or enhancement totherapeutic agent delivery. One such ESA method that has proven to beeffective in virtually all cell types is electroporation. Other methodsof electrically mediated delivery include iontophoresis, electroosmosis,electropermeabilization, electrostimulation, electromigration, andelectroconvection. These terms are used for illustrative purposes onlyand should not be construed as limitations in the invention.

The technique of electroporation utilizes the application of electricfields to induce a transient increase in cell membrane permeability andto move charged particles. By permeabilizing the cell membranes withinthe target tissue, electroporation dramatically improves theintracellular uptake of exogenous substances that have been administeredto the target tissue. The increase in cell membrane permeability andmolecular movement due to electroporation offers a method for overcomingthe cell membrane as a barrier to therapeutic agent delivery. Theapplication of electroporation as a technique for inducing EMTAD isadvantageous in that the physical nature of the technique allowselectroporation to be applied in virtually all tissue types.Accordingly, various aspects and embodiments of the invention discuss,but are not limited to, electroporation as a technique for inducingEMTAD.

Therapeutic Agents

The term “therapeutic agent” will be used in its broadest sense toinclude any agent capable of providing a desired or beneficial effect onliving tissue. Thus, the term will include both prophylactic andtherapeutic agents, as well as any other category of agent having suchdesired effects. Clearly, the scope of the present invention issufficiently broad to include the controlled delivery of any agent,however categorized. Therapeutic agents include, but are not limited topharmaceutical drugs and vaccines, and nucleic acid sequences (such assupercoiled, relaxed, and linear plasmid DNA, antisense constructs,artificial chromosomes, or any other nucleic acid-based therapeutic),and any formulations thereof. Such agent formulations include, but arenot limited to, cationic lipids, cationic polymers, liposomes, saline,nuclease inhibitors, anesthetics, poloxamers, preservatives, sodiumphosphate solutions, or other compounds that can improve theadministration, stability, and/or effect of the therapeutic agent.Additional benefits derived from certain agent formulations include theability to control viscosity and electrical impedance of theadministered agent, an important consideration for EMTAD applications.

In the case of nucleic acids, an example of a therapeutic agent would beplasmid DNA dissolved in a sodium phosphate solution with a competitivenuclease inhibitor such as aurintricarboxylic acid (ATA) added to theagent. In some embodiments using nucleic acid-based therapeutics, it mayalso be advantageous to incorporate a signaling peptide onto theconstruct. Potentially useful peptides include, but are not limited to,nuclear localization signals, endosomal lytic peptides, andtranscriptional control elements. These signals can enable improveddelivery and/or processing of the therapeutic agents delivered to thecells via EMTAD. This signaling can be accomplished through the use ofmethods as described in U.S. Pat. No. 6,165,720. While these techniquescan be utilized with other delivery systems, the ability of EMTAD toincrease the delivery of nucleic acid constructs to target tissues makesit particularly well suited for use with such signals.

Target Tissues

Target tissues well suited for EMTAD include both healthy and diseasedcells located in the epidermis, dermis, hypodermis, connective, andmuscle tissue. The technique can also be utilized for application inhealthy or diseased organs that must be accessed via minimally invasiveor other surgical means. Such target tissues include the liver, lungs,heart, blood vessels, lymphatic, brain, kidneys, pancreas, stomach,intestines, colon, bladder, and reproductive organs. One should notethat the desired therapeutic effect may be derived from agent deliveryto cell types normally located within the target tissues as well asother cell types abnormally found within said tissues (e.g.chemotherapeutic treatment of tumors).

As discussed previously, and depicted in FIG. 1, traditional EMTADsuffers from a lack of precision and reproducibility in the spatial andtemporal relationship between the administration of the therapeuticagent and the electrical signal. In contrast to the traditional EMTADapproach, the present invention describes methods and apparatus forcombined CTAA and ESA to provide a more advantageous clinicalapplication of EMTAD. This invention utilizes various aspects of CTAA inconjunction with ESA to provide reproducible, consistent, andefficacious therapeutic agent delivery. More specifically, the methodsand apparatus proposed herein provide spatial and temporal control overadministration of a therapeutic agent relative to the application ofelectrical signals, thereby improving the movement and/or uptake of saidagent in the target tissue.

Methods

In one aspect, the invention described herein provides methods forcontrolled administration of a therapeutic agent followed by ESA. Thesemethods consist of, but are not limited in scope or sequentialrelationship to, the determination of treatment parameters, patientpreparation procedures, CTAA, ESA, and additional measures.

Determination of Treatment Parameters

Treatment parameters are dictated by the desired dosing of thetherapeutic agent. Therapeutic agent dosing may depend on the particularindication or treatment application (such as the type and location ofthe target tissue), as well as various patient parameters (such as ageand body mass). Dosing of the therapeutic agent may be controlled byparameters pertaining to administration of the therapeutic agent andESA. Controllable parameters pertaining to CTAA include agent volume,agent viscosity, and injection rate. Controllable parameters pertainingto ESA include the characteristics of the electrical signals, the tissuevolume exposed to the electrical signals, and the electrode arrayformat. The relative timing and location of CTAA and ESA are parametersproviding further control over therapeutic agent dosing.

Patient Preparation

Patient preparation includes, but is not limited to, antisepticcleansing and anesthetic administration, including local or regional,nerve block, spinal block, epidural block, or general anesthesia. In thecase of intramuscular (IM) ESA, protocols to minimize the effects ofelectrical stimulation of the muscle may be taken, including thermalcontrol (e.g. cooling the muscle), administration of anesthetics, and/oralternative stimulation patterns sufficient for mitigation ofdiscomfort. One should ensure that the selected patient preparationtechniques do not adversely affect therapeutic efficacy, if acceptablealternatives exist. For example, it has been shown that certainanesthetics can have an undesirable effect on plasmid DNA-basedtherapies.

CTAA and ESA

In the practice of the method, the application of CTAA and ESA arecombined, enabling consistent and reproducible therapeutic agentdelivery. Two representative embodiments of apparatus suitable for CTAAinclude automatic injection devices and jet injectors.

CTAA Apparatus Embodiments

Turning now to the additional drawings, where like elements areidentified by like numerals throughout the figures, as depicted in FIG.2, in certain embodiments an automatic injection device 10 is utilizedas the means of controlled administration of therapeutic agents to thetarget tissue. As used herein, an automatic injection device is a devicethat is capable of administering a therapeutic agent to a patient at acontrolled rate through at least one hollow injection needle 12, such asa hypodermic needle, each with at least one orifice 14.

Conveniently, the automatic injection device 10 will utilize a housing16 to enclose, for example, a conventional disposable syringe 18,plunger 20 and needle 12 arrangement, together with the means necessaryto insert the needle into the patient and dispense the therapeutic agentthrough the needle (as described below). Administration of therapeuticagents with automatic injection device 10 is initiated by an operatoractivating trigger 22 and begins with the insertion of injection needle12 containing one or more orifices 14 through which the therapeuticagent can be transferred into the patient. Descriptions and examples ofautomatic injection devices which can find use in the present inventionare provided in U.S. Pat. Nos. 6,077,247 and 6,159,181, the entiredisclosures of which are incorporated by this reference.

Preferably, injection needle 12 is inserted into the patient by a drivemechanism 24 contained within automatic injection device 10. Preferably,injection device 10 also includes depth control means 26 for reliablycontrolling the depth of penetration of injection needle 12. Once needle12 is inserted, the therapeutic agent is transferred at a controlledrate from a suitable reservoir 28 through orifice 14 of needle 12 andinto the patient. It is also considered desirable to include a means toinhibit relative motion between the plunger and the body of the syringeuntil such time as the injection needle has reached the predeterminedlocation within the patient, and thereby minimize the distribution ofthe agent outside of the predetermined area of interest.

The automatic injection device 10 may contain a single injection needle12 or multiple needles, through which single or multiple types of agentsmay pass, depending upon the specific application. The energy source 30utilized to transfer the therapeutic agent from the reservoir 28 intothe patient is commonly compressed gas or a spring, though other sourcesmay be utilized.

Given that multiple applications for the present invention arecontemplated and that there are significant differences in body andtissue composition between patients, it is likely that reproducible andconsistent practice of the invention in a large patient population willdesirably include a means for adjusting the injection parameters. Suchinjection parameters include the needle size, injectant viscosity,injectant volume, concentration of therapeutics, and injection rate. Ameans for adjusting these parameters is desirable to compensate forvarious characteristics of the therapy recipient, including age, weight,dosing, target tissue type, and the target tissue depth, especially fortranscutaneous administration (which may be affected, among otherfactors, by the recipient's age and level of obesity).

In certain indications, a single-use and/or self-destructingneedle-syringe may be used as therapeutic agent reservoir 28, therebypreventing cross-contamination of blood-borne pathogens betweenrecipients. Similarly, protection is provided to the operator againstaccidental needle-stick injuries and resulting blood-borne pathogentransmission by using automatic injection devices that incorporate ameans of needle retraction 32 after use. This method of agentadministration is particularly useful in high-risk situations, such asinjecting patients infected with HIV, Hepatitis, or any otherblood-borne pathogens.

In one specific application of such an embodiment, an automaticinjection device is used for IM injection of plasmid DNA encoding for atherapeutic protein. Skeletal muscle has several characteristics thatmake it a desirable target tissue for this application. First, skeletalmuscle constitutes up to 40% of the average adult's body mass and iseasily accessible for transcutaneous administration of the plasmid. Inaddition, muscle cells rarely divide in vivo and thus, the introducedplasmid will not be lost during mitosis. Muscle cells are alsomulti-nucleated, thereby providing multiple targets for the plasmid onceit reaches the intracellular space. These characteristics enableprolonged expression and secretion of the protein into systemiccirculation. If the gene of interest can be transfected into an adequatenumber of muscle fibers, the tissue can produce the protein at levelssufficient to induce a biologic effect in patients. For example, ananemic patient may receive an IM injection of plasmid DNA encoding forthe protein erythropoietin (EPO), followed by electroporation. Upontreatment, transfected cells would produce and secrete the EPO protein,leading to an increase in hematocrit. The benefits of having such atreatment, which allows the body to manufacture its own EPO, are veryenticing. By introducing and expressing EPO in muscle usingelectroporation, the body would be able to produce EPO for an extendedperiod of time and patients may require boosters at substantiallyreduced time intervals.

In other embodiments of the present apparatus, as depicted in FIGS. 3and 4, a jet injector 100 is utilized as the means for CTAA to thetarget tissue. Examples of jet injection devices include: WIPOPublication Nos. WO0113975, WO0113977, and WO0009186. Similar to the useof an automatic injection device, administration of therapeutic agentswith a jet injector 100 is initiated by an operator activating trigger22 but transmission of the agent from a jet injector to the patientrelies on the penetration of a high-pressure stream 102 of such agentthrough an orifice 104 into the tissue. Although jet injection istypically accomplished without the use of a penetrating injectionneedle, in some cases the injection orifice 104 is located at theterminal end of a mini-needle used to bypass the outermost layers of atissue system. The high-pressure stream 102 of therapeutic agentgenerated by jet injector 100 then follows the path of least resistanceas it is forced through the tissue, resulting in a widely disperseddistribution of the therapeutic agent (see FIG. 4A). The jet injector100 may contain a single orifice 104 or multiple orifices for injection,through which single or multiple types of agents may be transferred,depending upon the specific application. The source of energy 30 used toactivate a plunger 106 to transfer the therapeutic agent from a suitablereservoir 28 through the injection orifice 104 is commonly compressedgas or a spring, but other energy sources can also be used.

In order to achieve reproducible and consistent agent administration,where the population is expected to exhibit variable patient parameters,the orifice size and shape, injectant pressure, injectant viscosity,injectant volume, concentration of therapeutics, and injection rate area few examples of the adjustable jet injection parameters which can becontrolled. Such adjustable parameters of the jet injector are necessaryto account for various characteristics of the therapy recipient,including age, weight, dosing, target tissue type, and the target tissuedepth, especially for transcutaneous administration (which may beaffected, among other factors, by the recipient's age and level ofobesity). Such adjustable parameters may also be necessary to ensurethat the agent is stable and viable when exposed to the pressure andshearing stress inherent to jet injection-mediated administration.

In the case of transcutaneous injection, the interface between theinjector orifice and skin is also critical in achieving reproducible andsafe administration; the spatial location of the jet injector should bemaintained for the duration of injection. To address this issue, incertain embodiments the jet injector can be provided with the means ofmaintaining a slight vacuum 108 at the device/tissue interface tofacilitate administration of the technique and stabilize the spatiallocation of the unit. Interface stabilization may also be accomplishedwith the use of adhesives, with the temporary application of restraintmechanisms, or any combination thereof.

A significant concern with jet injection technology is ballisticcontamination, in which the jet injection builds pressure in the tissuethat is greater than the pressure in the injector, causing a smallbackflow of blood or other bodily fluids onto the device. In response tothis problem, a single-use, self-destructing vial 110 may be used fortherapeutic agent containment of the jet injector. This preventscross-contamination of blood-borne pathogens between recipients.Similarly, since most jet injectors have no needle, protection isprovided to the operator against accidental needle-stick injuries andresulting blood-borne pathogen transmission. Such a form of needlelessinjection is particularly useful in high-risk situations, such asinjecting patients infected with HIV, Hepatitis, or any otherblood-borne pathogens.

ESA Parameters

One representaive form of ESA is electroporation, but all forms of ESAshare certain common features desirable for the efficient application ofthe techniques to EMTAD. A critical aspect of electroporation is thegeneration and propagation of electroporation-inducing electrical fieldswithin the region of tissue targeted for therapeutic agent delivery.There are several methods for generating such fields in vivo, includingsurface and penetrating electrode arrays. The present invention can bepracticed with any electrode system suitable for propagating theelectrical signals within the targeted region of tissue. The specificcharacteristics of the electrode systems will determine if that type ofelectrode is suitable for use in a given application.

With surface style electrode arrays, an electrical field is propagatedthrough the surface of the skin and into the target tissue.Unfortunately, surface style electrode arrays, such as plates ormeander-type electrodes (as described in U.S. Pat. No. 5,968,006), areinefficient or impractical for most indications. The electrodes aretypically unable to target regions beyond the most superficial tissues,they cannot be applied in a reliable fashion, and their use often canresult in burning and scarring at the site of application.

Penetrating electrodes are typically more desirable for most forms ofESA, and particularly for electroporation. Penetrating electrodes aredefined as conductive elements whose size and shape are sufficient toenable insertion through the matter covering a tissue of interest, suchas skin covering muscle tissue, or the outer layer(s) of such tissue.There are numerous embodiments of penetrating electrode array systems,including bipolar and multielement electrode arrays. The simplestpenetrating electrode array is the bipolar system, which consists of twopenetrating electrodes connected to the opposite poles of a pulsegenerator. Systems of penetrating bipolar electrodes have been usedextensively in preclinical studies of electroporation. However, thenon-uniform electrical fields characteristic of bipolar electrodes makesthem an inefficient means for generating threshold levels sufficient forelectroporation throughout a target region of tissue. More complexsystems have been developed using three or more electrodes to comprise amultielement array. The specific geometrical arrangement and activationpattern of these multi-element arrays can result in superior performancecharacteristics compared to the bipolar approach.

For many clinical indications, a grid-based multielement electrodearray, such as the TriGrid™ electrode system, is the most advantageousmeans of applying ESA in accomplishing the therapeutic objective. TheTriGrid™ system, disclosed in U.S. Pat. No. 5,873,849 (the entiredisclosure of which is incorporated herein by reference), consists ofslender penetrating electrodes with a geometry and activation patterndesigned to maximize field uniformity within a targeted volume oftissue. As a result, the ESA effect can be achieved throughout thetarget volume with minimized variability due to the electrical fieldspropagated within the tissue.

The TriGrid™ design considerations ensure that the threshold fieldstrengths required to achieve electroporation are propagated throughoutthe target tissue while minimizing the amount of tissue exposed toexcessively high fields that could result in tissue injury. These moreuniform electric field distributions are achieved by simultaneouslyactivating more than two of the electrodes within the array, therebyreinforcing the electric fields being propagated in the more centraltissues away from the electrodes. Since the probability of achievingmembrane permeability can also depend on the physical dimensions andorientation of the cell, the sequential propagation of electrical fieldsat different angles increases the likelihood that the electroporationeffect can be achieved in any given cell.

As depicted in FIG. 5, each set of four electrodes establishing agenerally diamond shaped multielement array is called a Unit TriGrid™50. Any number of Unit TriGrid™ “modules” can be integrated together andexpanded to form electrode arrays with different geometries capable oftreating various shapes and volumes of tissue. Several importantclinical benefits are derived from the use of the expandable TriGrid™electrode array system. First, the system allows the patient to betreated with a single placement of the electrodes, thereby minimizingthe time required for the procedure and reducing any discomfortassociated with repeated penetration and stimulation of an electrodearray. Second, by controlling the amount of tissue exposed to theESA-induced electrical fields, the grid based electrode formatessentially provides a method for accurately adjusting the dose of thetherapeutic agent. Finally the TriGrid™ is likely to result inconsistent application of the treatment from patient-to-patient andoperator-to-operator since it reduces uncertainty associated with theamount of tissue targeted by threshold level electroporation-inducingelectrical fields.

In certain preferred embodiments, a TriGrid™ array is utilized as themode of establishing electroporation-inducing electrical fields. A highvoltage electrical state sequencer and electrical signal generator isconnected to each of the electrodes through conductive cables, thusgenerating an electroporation-inducing electrical field. In order toachieve reproducible and consistent therapeutic efficacy providedvariable patient parameters, the electrode size, shape, and surfacearea, the electrical field strength (typically 50–2000 volts percentimeter), the frequency of stimulation (typically 0.1 Hertz to 1megahertz), the waveform (such as bipolar, monopolar, AC, capacitivedischarge, square, sawtooth, or any combination thereof) and theelectrical signal duration (typically 1 microsecond to 100 milliseconds)are a few examples of the adjustable electroporation-inducing electricalfield parameters. Selection of such adjustable electroporationparameters is based, among other factors, on the agent to be delivered,the dosing, the specific application and method of administration, thetype and location of the target tissue, and the volume to be treated. Inother embodiments, plate electrodes, bipolar, and other multielementelectrode arrays may be utilized as the mode of generatingelectroporation-inducing electrical fields; however, the TriGrid™ arrayis superior in accomplishing the therapeutic objective for mostindications.

Additional Procedures

There are several additional procedures that may be included in theapplication of CTAA and ESA, which assist in the accomplishment of thedesired therapeutic objective. For instance, after the therapeutic agenthas been administered it may be advantageous to utilize techniques toenhance agent distribution within the tissue by molecular movement.Suitable techniques to enhance molecular movement and homogeneityinclude iontophoresis, electroosmosis, ultrasound, and thermal means. Inthe case of iontophoresis and electroosmosis, it may be desirable to usethe same electrodes that deliver electroporation; however, additionalelectrodes may be used. The administration of dexamethasone andpoloxamer, among other agents that can affect the state of the cellmembrane, have been shown to enhance various aspects of electroporationtherapy. Following treatment, precautionary measures may be taken tocleanse the treatment site.

Integrated CTAA/ESA Apparatus

There are several embodiments suitable for achieving spatially andtemporally controlled TAA relative to application of electrical signals.A preferred embodiment providing spatial and temporal control is anapparatus wherein therapeutic agent administration and ESA areaccomplished by means of an integrated unit. The integrated unit mayutilize administration means such as an automatic injection device (FIG.2) or a jet injector device (FIG. 3) as the mode of CTAA, withelectroporation-inducing electrical fields as the mode of ESA. Such anembodiment does not limit this invention of combined employment of CTAAand electroporation to an integrated unit, or by said means. However,integration of such an apparatus provides improved temporal and spatialcontrol that may not be as accurately achieved with application ofindividual CTAA and electroporation units.

Embodiments

The appropriate temporal and spatial generation of anelectroporation-inducing electrical field with respect to the timing andlocation of the therapeutic agent administration is critical forachievement of consistent and reproducible therapeutic effects. Forinstance, if the operator administers a therapeutic agent with onedevice, and then employs another device for establishment of anelectroporation-inducing electrical field, there may be variability inthe relative temporal and spatial applications of CTAA andelectroporation. Such inter-patient variability, due to inter-operatorvariability, can result in highly undesirable therapeuticinconsistencies. In the practice of the proposed integrated unit,operator training and variability are significantly reduced, since thespatial and temporal relationship of the CTAA and electroporation arecontrolled through the use of an integrated application system andcontrol means rather than the operator. Furthermore, operator error byinconsistent and inaccurate temporal and spatial establishment of theelectroporation-inducing electrical field relative to the therapeuticagent administration may be minimized, enabling reproducible andconsistent therapeutic efficacy and dosing.

In all embodiments, administration of the therapeutic agent is performedin a spatially and temporally controlled fashion relative to ESA.Accordingly, spatial control and temporal control are both addressedbelow as separate aspects. Though addressed separately, these aspectsmay be combined in all such embodiments to form an integratedapplication unit providing both spatial and temporal control overadministration of the therapeutic agent. The particular combination ofembodiments employed is dictated by the specific indication.

Embodiments Providing Temporal Control

In the combination of therapeutic agent application and electroporation,the need for temporal control is twofold: 1) the ability to administerthe therapeutic agent at a controlled rate, and 2) the ability tocontrol the sequence and timing of TAA and electroporation application.In the present invention, the former issue is addressed by the use of anautomated injection apparatus, and the latter is addressed byintegrating this automated injection apparatus with an appropriate meansfor the application of electroporation.

The rate of therapeutic agent administration into the tissue is largelycontrolled by the design of the administration apparatus. Two commonadministration methods that provide suitable control over the rate ofagent administration are automatic injection devices 10 and jet injectordevices 100. For both administration methods, an energy source 30 isrequired to transfer the therapeutic agent from a suitable reservoir 28in the device through an orifice 14, 104 and into a target region oftissue at a controlled rate. Suitable sources of energy for automaticinjection devices and jet injectors include springs, compressed gas, andelectromechanical means. The rate of administration may be controlled byregulation of several parameters, including the energy source (e.g.spring constant, gas pressure, voltage, or current), needle diameter,orifice diameter, and agent viscosity. The parameters may be selected bythe operator prior to administration to set the desired rate. However,once administration is initiated, the rate is operator-independent, andthe agent is transferred at a predetermined rate.

In the practice of the present invention, an integrated unit is appliedto the therapy recipient, allowing the desired sequence and timing ofCTAA and electroporation to be achieved in a controlled and reliablefashion without undesirable time delays and/or multiple deviceplacements. For example, one treatment protocol calls for theadministration of plasmid DNA encoding for a therapeutic protein,followed by generation of an electroporation-inducing electrical field,and then followed by administration of dexamethasone. In the absence ofthe present invention, there would be three different device placements,with an unavoidable time interval in between the operator's placementand activation of each device. This complexity increases the probabilitythat inter-patient variability would arise from inconsistent temporalapplication of each device by individual operators who are likely tohave substantially different skill levels. This complexity andvariability is compounded in the case where multiple application sitesare necessary to get adequate dispersal of the agent to a treatmentregion within the target tissue. Using the described invention, however,only a single device is required, enabling any desired sequence of CTAA,electroporation, and additional procedures to be applied with minimalspatial and temporal variability and limitations. This feature iscritical for agents that must reach the interior of the target cells tomaintain efficacy. The treatment may not be consistently and reliablyaccomplished with multiple units, where temporal limitations andinjection rate variability may be present in the treatment regimen. Forexample, when plasmid DNA is exposed after in vivo administration to theextracellular environment, physiological enzymes (DNases) break it down.Since the exact rate of enzymatic activity is dependent on the specificpatient, minimizing the time interval between CTAA and electroporationallows more accurate control over the treatment dosage. In the in vivoenvironment, viability must be maintained by expeditious entry of thetherapeutic agent to the interior of the target cells, and this may notbe as consistently and reliably achieved with multiple units as it maybe with an integrated unit, with which time lags are not a significantlimitation and enzymatic activity is reduced as a source of variability.

Embodiments Providing Spatial Control

There are several embodiments suitable for achieving spatiallycontrolled therapeutic agent administration. One embodiment suitable forspatially controlled therapeutic agent administration is a template 52,as depicted in FIGS. 5A–D, containing a single (FIG. 5A) or a plurality(FIGS. 5B–D) of ports 54 designed to accommodate injection orificescharacteristic of a jet injector or automatic injection device at afixed location relative to electrodes 56 suitable for generation ofelectroporation-inducing electrical fields. Additionally, the use ofports 54 provides improved angular and depth control over administrationof the therapeutic agent. The template 52 may contain a single orplurality of port interlocks for administration device stabilization,through which any combination of automatic injection devices or jetinjectors may be connected and employed in a spatially controlledfashion.

A preferred embodiment of the invention that provides spatial andtemporal control in the delivery of therapeutic agents is an apparatuswherein CTAA and ESA are accomplished by means of an integrated unit.The integrated unit may utilize administration methods such as anautomatic injection device or a jet injector as the mode of CTAA, withelectroporation-inducing electrical fields as the preferred mode of ESA.There may also be indications for which any combination of single ormultiple automatic injection devices and jet injectors is beneficial.For instance, the TriGrid™ electrode array allows for virtually alltarget tissue volumes and shapes to be treated with a single placementof the array. A device with multiple agent administration means wouldthen allow for reproducibly co-localized CTAA and electroporation to awide variety of target tissues with a single placement of the integratedunit. The number of administration means implemented with respect to thenumber of Unit TriGrid™ arrays may depend on various treatmentparameters, including the nature of the agent to be delivered, thedesired dosing, the type and location of the target tissue, and thevolume to be treated.

In the practice of the invention utilizing such embodiments, theintegrated unit is placed in the desired location, the administrationdevice is employed to administer the therapeutic agent, and theelectrode array of electrodes is activated in the target tissue, allwithout spatial relocation of the integrated unit. Desirably, theelectrode array can be provided with the means to adjust the spatialrelationship to the orifice, for example, by providing retractableelectrodes. In such an embodiment, the electrodes would then be deployedupon command, and activated at the appropriate time, in order to effectthe EMTAD treatment. The electroporation-inducing electrical field isthereby established, enabling delivery of the therapeutic agent to theinterior of the target cells, and the electrode array is then retractedfrom the target tissue. This single-placement device minimizes spatialvariability and limitations on the sequential application of CTAA andelectroporation, while enabling highly accurate control over spatialparameters, such as the application of CTAA relative to electroporation.This is especially important for electroporation, where reproducibleco-localization between the therapeutic agent and the target tissue isoptimal for therapeutic agent delivery in consistent, efficacioustherapies.

In all embodiments described above, additional distributional control isderived from combination of rate control with a template-based device,or as a component of an integrated unit. For example, if a plurality ofadministration devices is used, then the spatial and temporalrelationship between location and timing of injections is readilycontrolled, thereby providing a more consistent, rapid, and homogeneousdistribution of the therapeutic agent.

Description of an Exemplary Integrated Unit Embodiment

As depicted in FIGS. 2, 3, 6 and 7, the integrated unit may use anautomatic injection device 10, jet injector 100, or any combinationthereof as the mode of CTAA. For certain indications, an automaticinjection device 10 may be the preferred mode of CTAA. The automaticinjection device may use standard syringes and needles, fixed ornon-fixed. A disposable, self-destructible, and/or pre-filledneedle-syringe unit 18 may be preferable for certain indications. Theneedle should be positioned within a housing 16 that incorporates apenetration-depth controlling means 26, thereby preventing accidentalneedle stick. For added safety, the automatic injection device mayprovide retraction of the needle once insertion and injection has beencompleted. Accidental discharge prevention means may also be desirable.For other indications, a needleless or mini-needle jet injector 100 maybe the preferred mode of CTAA. A disposable, self-destructible, and/orpre-filled vial 110 containing the agent may be preferable for certainindications. If the jet injector contains a mini-needle, as may be thecase for transcutaneous penetration, the mini-needle should bepositioned to prevent accidental needle stick. Likewise, the jetinjector may provide retraction of the mini-needle once insertion andinjection has been completed. It may also be desirable to haveaccidental discharge prevention means. For all administration devicescontaining needles and mini-needles, it may be desirable to have thedeployed or retracted state of said needles and mini-needles displayedto the operator.

The integrated unit may use the TriGrid™ array as the mode ofimplementing ESA, with elongate electrodes 56 disposed according to thetissue shape and volume to be treated. In one embodiment of theinvention, an integrated apparatus 200, shown in FIGS. 6 and 7, includesan array of electrodes 202 contained within a separable, and optionallydisposable, sub-assembly 204 that can be easily attached to and removedfrom the main unit 206, allowing for controlled-usage and disposableelectrodes. As described above, certain embodiments of the inventionemploy retractable electrodes 208, as it is preferable if the electrodescan be contained within the apparatus 200 prior to their deployment intothe target tissue. In cases of transcutaneous application, retractableelectrodes would allow for improved operator safety, reduced risk of aloss in electrode sterility prior to insertion and mitigation of anybelonephobia for the patient. Control over movement of such electrodesmay be provided by spring, compressed gas, or other appropriate energysource 210 in conjunction with a drive mechanism 212 to extend theelectrodes 208 through port 228 and into the patient. The electrodes 208may be actuated individually or as a unit, and preferably, the deployedor retracted state of the electrodes is displayed, either individuallyor as a unit, to the operator. As with automatic and jet injectiondevices, the use of retractable needle-type electrodes 208 may reducebelonephobia experienced by the therapy recipient, while providing theoperator with increased safety to blood borne pathogens and otherneedle-stick related injury.

Electrical continuity is necessary between the desirably activeelectrodes and the electrical signal generator. Therefore, inembodiments where the electrode array is detachable, a continuous andreliable electrical connection 214 should be readily achieved betweenthe electrodes 208 within the array 202 and the apparatus 200. Theinvention also includes an electrical signal generating means 216 inconductive communication with the apparatus 200. The nature of theelectrical signal generating means 216 will depend on the desiredapplication. In some embodiments, the electrical signal generating means216 can be located 226 within the integrated apparatus 200. Desirably,in such an embodiment the connections necessary to maintain electricalcontinuity between the electrodes and the electrical signal generatorare housed internal to the apparatus. In the case of external electricalsignal generating means 216, as depicted in FIG. 7, a cable 218 betweenthe generator 216 and the apparatus 200 is provided with a suitableconnector 220 located on the apparatus 200 in a manner to minimizeinterference with operator use. As electrodes 208 may be retracted ordeployed, conductive housing 222 is provided for electrical connectionbetween deployed electrodes and the electrical signal generator 216.Conductivity may also be accomplished by connection 230 through theelectrode drive mechanism 212 and/or energy source 210.

Selection of electrode parameters is a critical component ofelectroporation therapy. Electrode parameters include diameter, tipprofile, length, conductivity, and materials. The electrodes may behollow, allowing for the administration of anesthetics or other agents.The electrodes may also be coated with anesthetics and/or lubriciousagents for pain mitigation and ease of insertion. The electrodeparameter selection is dictated by several treatment factors, includingproperties of the target tissue, tissue volume to be treated, and chargeinjection/current densities at the electrode-tissue interface. Forexample, in the transcutaneous application of electroporation, trocartip 58 (polyhedron with three faces) electrodes with a nominal diameterof 0.005″ to 0.05″ are desirable. The inter-electrode spacing 60 andpenetration depth define the volume of tissue to be treated. Forelectroporation in healthy tissues, it is often desirable that theelectrodes have a sufficiently inert surface material 62 which iselectrochemically stable and will not exhibit substantialoxidation-reduction reactions with the interstitial environment whenexposed to high charge injections that may occur as a result of ESA.Such surfaces may be platinum, platinum-iridium, iridium, iridium-oxide,gold, and titanium nitride. Depending upon the material chosen, it maybe desirable for cost and structural reasons to deposit these inertmetals to the surface of a base metal. Appropriate base metals include,but are not limited to titanium, tungsten, stainless steel, and MP35N.

The process of deposition for the desired electrochemically stablecoating may consist of chemical or physical vapor deposition, creatingcoatings on the order of tenths to hundreds of microns. The level ofcharge injection and irreversible oxidation-reduction reactions shouldbe considered when choosing a sufficiently inert material and depositionthickness. In order to target the ESA electrical fields to a specifiedregion, including elimination of non-homogeneous electrical fields fromthe electrode tips 64, dielectric coatings 66 such asPolytetrafluoroethylene (PTFE), Parylene, and Silicon Carbide may bedeposited onto the electrode at thicknesses of tenths to hundreds ofmicrons. The pinhole size and dielectric strength of such coatingsshould be considered when choosing an appropriate dielectric materialand thickness.

A further aspect of the invention provides a system wherein thesequential timing and functions of the integrated CTAA-ESA unit arecontrollable. This may provide, for example, presettable procedureparameters, procedure automation, and/or closed loop systemic control.The control system 224 of the integrated unit may regulate parameterspertaining individually to CTAA and electroporation, and collectively totheir integrated function. In certain embodiments, the control systemmay regulate the effective administration and dosing of therapeuticagents by adjustment of CTAA and electroporation parameters. Othertreatment parameters to be controlled include application of a localanesthetic, placement and removal of retractable electrodes,administration of additional therapeutics, and the timing and durationof each step of the procedure.

In certain embodiments, the control system and means for electricalsignal generation are incorporated into a portable or handheld unit foruse with the integrated CTAA-ESA apparatus. For portability, a spring orcompressed gas may be used as an energy source 30 acting through a drivemechanism 232 as a means of therapeutic agent transfer, and desirablyhaving multiple settings for operator-selectable control over the rateof transfer in therapeutic agent administration. If a spring is used,then the loaded and unloaded state of the spring could be displayed tothe operator. If compressed gas is used, a qualitative or quantitativepressure level could be displayed to the operator. In this embodiment,the integrated unit may be powered by battery, capacitor bank, or pulseforming network that is energized by use of a portable station, solarcells, or other electrical sources.

All patents and patent applications cited in this specification arehereby incorporated by reference as if they had been specifically andindividually indicated to be incorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and Example for purposes of clarity andunderstanding, it will be apparent to those of ordinary skill in the artin light of the disclosure that certain changes and modifications may bemade thereto without departing from the spirit or scope of the appendedclaims.

1. An apparatus for the intracellular delivery of a therapeutic agent toa predetermined site within the tissue of a patient comprising: meansfor the administration of said therapeutic agent to said patientcomprising a reservoir for the therapeutic agent, at least one orificethrough which the agent is administered, and an inanimate source ofenergy sufficient to transfer a predetermined amount of the therapeuticagent from said reservoir through said orifice to the predetermined sitewithin the tissue of the patient; a plurality of penetrating electrodesarranged with a predetermined spatial relationship relative to saidorifice; and means configured for generating an electrical field whichfacilitates the intracellular delivery of said therapeutic agent saidmeans operatively connected to said electrodes.
 2. The apparatus asrecited in claim 1 wherein the electrodes comprise a subassembly thatcan be separated from the orifice.
 3. The apparatus as recited in claim1 further comprising means for adjusting the predetermined spatialrelationship between said electrodes and said orifice.
 4. The apparatusas recited in claim 3 wherein said means for adjusting the spatialrelationship comprises a source of energy.
 5. The apparatus as recitedin claim 1 wherein the electrodes comprise a conductive,electrochemically stable compound.
 6. The apparatus as recited in claim1 wherein the electrodes comprise a conductive metal coated with aconductive, electrochemically stable compound.
 7. The apparatus asrecited in claim 5 wherein said conductive, electrochemically stablecompound consists of at least one of the following materials: titaniumnitride, platinum, platinum iridium, iridium oxide.
 8. The apparatus asrecited in claim 1 wherein the means for administration of thetherapeutic agent is a jet injector.
 9. The apparatus as recited inclaim 8 wherein the source of energy to transfer the therapeutic agentis at least one compressed gas.
 10. The apparatus as recited in claim 8wherein the source of energy to transfer the therapeutic agent is atleast one spring.
 11. The apparatus as recited in claim 8 wherein thejet injector comprises means for controlling the rate at which the agentis transferred through the orifice.
 12. The apparatus as recited inclaim 1 wherein the means for administration of the therapeutic agent isan automatic injection device.
 13. The apparatus as recited in claim 12wherein said reservoir is a syringe including a penetrating hypodermicneedle.
 14. The apparatus as recited in claim 12 wherein the source ofenergy to transfer the therapeutic agent is at least one compressed gas.15. The apparatus as recited in claim 12 wherein the source of energy totransfer the therapeutic agent is at least one spring.
 16. The apparatusas recited in claim 13 wherein the automatic injection device comprisesmeans for controlling the depth of penetration of said needle into thepatient.
 17. The apparatus as recited in claim 12 wherein the automaticinjection device comprises means for controlling the rate at which theagent is transferred through the orifice.
 18. The apparatus as recitedin claim 6 wherein said conductive, electrochemically stable compoundconsists of at least one of the following materials: titanium nitride,platinum, platinum iridium, iridium oxide.
 19. The apparatus as recitedin claim 1 wherein the means for generating an electrical field isconfigured to induce an electrical field of from approximately 50 toapproximately 300 V/cm between at least two of said electrodes.
 20. Theapparatus as recited in claim 1 wherein die means for generating anelectrical field is configured to deliver a signal for a duration offrom approximately 1 microsecond to approximately 100 milliseconds andat a frequency of from approximately 0.1 Hertz to approximately 1megahertz to at least two of said electrodes.